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        Reliability of human cryopreserved hepatocytes and liver microsomes as in vitro systems to predict metabolic clearance

        Author
        Stringer, R.
        Nicklin, P.L.
        Houston, J.B.
        Attention
        2299/11791
        Abstract
        A total of 110 drugs, selected to cover a range of physicochemical and pharmacokinetic properties, were used to explore standard approaches to the prediction of in vivo metabolic clearance using drug-depletion profiles from human liver microsomes (HLMs) and cyropreserved hepatocytes. A total of 41 drugs (37% of the compounds tested) showed measurable depletion rates using HLMs (depletion by 20% or more over the time course). The most reliable correlations in terms of bias (average fold error (AFE) = 2.32) and precision (root mean square error (RMSE) = 3501) were observed by comparing in vivo intrinsic clearance (CLint), calculated using the parallel-tube model and incorporating the fraction unbound in blood, with in vitro CLint adjusted for microsomal binding. For these reference drugs, 29% of predictions were within two-fold of the observed values and 66% were within five-fold. Compared with HLMs, clearance predictions with cryopreserved hepatocytes (57 drugs) were of similar precision (RMSE = 3608) but showed more bias (AFE = 5.21) with 18% of predictions within two-fold of the observed values and 46% within five-fold. However, with a broad complement of drug-metabolizing enzymes, hepatocytes catalysed measurable CLint values for a greater proportion (52%) of the reference compounds and were particularly proficient at defining metabolic rates for drugs with predominantly phase 2 metabolic routes.
        Publication date
        2008-10-01
        Published in
        Xenobiotica
        Published version
        https://doi.org/10.1080/00498250802446286
        Other links
        http://hdl.handle.net/2299/11791
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